Importin-β specific nuclear transport defects recapitulate phenotypic and transcriptional alterations seen in neurodegeneration

Defects in Nucleocytoplasmic transport have been implicated as an important neurodegenerative pathway in ALS/FTD. Here, we show that a NemfR86S mutation results in the disruption of NCT both in vitro and in vivo. These disruptions are specific to Importin-{beta} nuclear import, and result in the nuclear loss and cytoplasmic gain of NEMF, Importin-{beta}, and TDP-43. We show that a transient nuclear import block is capable of inducing the mis-localization of TDP-43 and is associated with altered transcriptional expression of ALS, FTD, and AD/ARD genes. Taken together, these findings show that disrupted Importin-{beta} nuclear import, whether through genetic forms such as Nemf mutations, or through pharmacological inhibition, is the primary driver of TDP-43 pathology, disease-related transcriptional alterations, and neurodegeneration.